Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

Abstract

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.

• Authors: Maya Chopra, Meriel McEntagart, Jill Clayton-Smith, Konrad Platzer, Anju Shukla, Katta M Girisha, Anupriya Kaur, Parneet Kaur, Rolph Pfundt, Hermine Veenstra-Knol, Grazia M S Mancini, Gerarda Cappuccio, Nicola Brunetti-Pierri, Fanny Kortüm, Maja Hempel, Jonas Denecke, Anna Lehman, CAUSES Study, Tjitske Kleefstra, Kyra E Stuurman, Martina Wilke, Michelle L Thompson, E Martina Bebin, Emilia K Bijlsma, Mariette J V Hoffer, Cacha Peeters-Scholte, Anne Slavotinek, William A Weiss, Tiffany Yip, Ugur Hodoglugil, Amy Whittle, Janette diMonda, Juanita Neira, Sandra Yang, Amelia Kirby, Hailey Pinz, Rosan Lechner, Frank Sleutels, Ingo Helbig, Sarah McKeown, Katherine Helbig, Rebecca Willaert, Jane Juusola, Jennifer Semotok, Medard Hadonou, John Short, Genomics England Research Consortium, Naomi Yachelevich, Sajel Lala, Alberto Fernández-Jaen, Janvier Porta Pelayo, Chiara Klöckner, Susanne B Kamphausen, Rami Abou Jamra, Maria Arelin, A Micheil Innes, Anni Niskakoski, Sam Amin, Maggie Williams, Julie Evans, Sarah Smithson, Damian Smedley, Anna de Burca, Usha Kini, Martin B Delatycki, Lyndon Gallacher, Alison Yeung, Lynn Pais, Michael Field, Ellenore Martin, Perrine Charles, Thomas Courtin, Boris Keren, Maria Iascone, Anna Cereda, Gemma Poke, Véronique Abadie, Christel Chalouhi, Padmini Parthasarathy, Benjamin J Halliday, Stephen P Robertson, Stanislas Lyonnet, Jeanne Amiel, Christopher T Gordon
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 108 Issue 6 Pg. 1138-1150 (06 03 2021) ISSN: 1537-6605 [Electronic] United States
• PMID: 33909992 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 American Society of Human Genetics. All rights reserved.

Chemical References

• ANKRD17 protein, human
• RNA-Binding Proteins

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• Craniofacial Abnormalities (etiology, pathology)
• Female
• Haploinsufficiency
• Heterozygote
• Humans
• Infant
• Intellectual Disability (etiology, pathology)
• Language Development Disorders (etiology, pathology)
• Loss of Function Mutation
• Male
• Pedigree
• Phenotype
• RNA-Binding Proteins (genetics, metabolism)
• Signal Transduction
• Syndrome
• Young Adult